Akt isoforms differentially regulate neutrophil functions

• Published in: Blood Vol. 115; no. 21; pp. 4237 - 4246
• Main Authors: Chen, Jia, Tang, Haiyang, Hay, Nissim, Xu, Jingsong, Ye, Richard D.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 27.05.2010; Americain Society of Hematology; American Society of Hematology
• Series: Phagocytes, Granulocytes, and Myelopoiesis
• Subjects: Animals; Biological and medical sciences; Biological Transport, Active; Cell Degranulation; Cell Movement; Hematologic and hematopoietic diseases; In Vitro Techniques; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidases - metabolism; Neutrophil Activation - drug effects; Neutrophil Activation - physiology; Neutrophils - drug effects; Neutrophils - physiology; Phagocytes, Granulocytes, and Myelopoiesis; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt - deficiency; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - physiology; Signal Transduction; Superoxides - metabolism; Tetradecanoylphorbol Acetate - pharmacology; Akt protein kinase; Molecular form; Neutrophil; Hematology; Granulocyte
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-11-255323

In neutrophils, the phosphoinositide 3-kinase/Akt signaling cascade is involved in migration, degranulation, and O2− production. However, it is unclear whether the Akt kinase isoforms have distinct functions in neutrophil activation. Here we report functional differences between the 2 major Akt isoforms in neutrophil activation on the basis of studies in which we used individual Akt1 and Akt2 knockout mice. Akt2−/− neutrophils exhibited decreased cell migration, granule enzyme release, and O2− production compared with wild-type and Akt1−/− neutrophils. Surprisingly, Akt2 deficiency and pharmacologic inhibition of Akt also abrogated phorbol ester-induced O2− production, which was unaffected by treatment with the phosphoinositide 3-kinase inhibitor LY294002. The decreased O2− production in Akt2−/− neutrophils was accompanied by reduced p47phox phosphorylation and its membrane translocation, suggesting that Akt2 is important for the assembly of phagocyte nicotinamide adenine dinucleotide phosphate oxidase. In wild-type neutrophils, Akt2 but not Akt1 translocated to plasma membrane upon chemoattractant stimulation and to the leading edge in polarized neutrophils. In the absence of Akt2, chemoattractant-induced Akt protein phosphorylation was significantly reduced. These results demonstrate a predominant role of Akt2 in regulating neutrophil functions and provide evidence for differential activation of the 2 Akt isoforms in neutrophils.